Antifungal Therapy Flashcards
What is the MOA of Amphotericin B?
- Binds sterols in cell membrane of eukaryotes, increasing cell permeability and causing leakage of nutrients and electrolytes
- Greater affinity for ergosterol (fungi) than cholesterol (humans)
What are some signs of acute Amphotericin B toxicity (ie. occurring during infusion)?
- Fever
- Vomiting
- Mylagia
- Anaphylaxis
Signs of acute amphotericin B toxicity are most commonly seen with what type of formulations? How can this be reduced?
Lipid; can be reduced by slowing infusion rate
What are some signs of chronic Amphotericin B toxicity?
-
NEPHROTOXICITY
- dose-limiting, typically cumulative effect, can be reduced w/ some lipid forms
- Weight loss
- Non-regenerative anemia
What are some characteristics of the formulation Amphotericin deoxycholate (Fungizone)?
- Not lipid complexed
- Highly protein bound
- Accumulates in liver, kidneys, and lungs - check renal values/USG
- __Should be diluted with sterile H2O and D5W
- Wide distributions in tissues and inflammatory exudates
- Poor penetration: bones, brain, CSF, aqueous/vitreous humors, resp secretions, uninflamed body cavities
What are some characteristics of the formulation Amphotericin cholesteryl sulfate (Amphocil)?
- Lipid complex
- Taken up by macrophages
- Highly concentrated in liver, spleen, lung (MPS organs)
- Poor penetration: kidney, stomach, SI, bone marrow, brain/CSF
What are some characteristics of the formulation liposome encapsulated Amphotericin (AmBisome)?
- Lipid complex
- Taken up by macrophages to lesser extent (d/t small size)
- Highly concentrated in liver, spleen, lung, kidney - high renal concentration
- Best CSF penetration of amphotericin formulations
What are some characteristics of the formulation lipid complexed amphotericin (Abelcet)?
- Lipid complex
- Rapid uptake by MPS (large particle)
- Higher concentration in liver, spleen, lung
What is the spectrum for Amphotericin B?
- Blasto
- Histo
- Crypto
- Coccidiodies
- Aspergillus (some resistance)
Why is Amphotericin B not as regularly used today? Why might you still reach for it?
- Has been largely displaced by safer (less nephrotoxic) drugs
- used in patients in which finances are limited (although safer, lipid-complexed forms are $$$ too)
Describe Flucytosine
- Converted to fluorouracil w/in fungal organism (yeast) and interferes w/ DNA synthesis
- Good oral absorption
- Crosses BBB/CSF
- Effective vs: Crypto and Candida
- Ineffective vs. Aspergillus
- Synergistic w/ amphotericin B
- rapid resistance
What are the side effects of flucytosine?
- Nephrotoxicity
- Drug eruptions (dogs)
- Thrombocytopenia? (cats)
Describe characteristics of azole derivatives
- Inhibit sterol (via cP450), nucleic acid, trig, and fatty acid synthesis
- generally less toxic than amphotericin B
- Fungistatic at low concentrations, fungicidal at high concentrations (not achieveable systemically)
- Hepatic metabolism (cytochrome P450) **drug interactions
Describe characteristics of ketoconazole
- PO or topical
- Variable oral absorption (improved w/ fatty meal/acid - NO antacids)
- Protein bound
- Good penetration of most tissues and body fluids
- Poor penetration of CNS, eye, and seminal fluid
What are the side effects of ketoconazole?
- Nausea/vomiting, decreased appetite (minimized w/ meals/divided doses)
- Hepatotoxicity (usually reversible)
- Occ. Thrombocytopenia
- Anemia
- Teratogenic
- Cortisol suppression
What is the spectrum for ketoconazole?
- Candida
- Malassezia
- Histo
- Blasto
- Coccidioides
**Less effective vs. Aspergillus, Crypto, Sporothrix
What are some concerns when treating with ketoconazole?
- It has a very slow onset of action, so may need to treat severe dz w/ amphotericin B first
- Relapses are common - treat at least 4 weeks beyond resolution of clinical dz
Describe itraconazole
- PO or IV
- Variable oral absorption
- capsules (improved w/ fatty meal/acid)
- oral solution (improved in fasted state)
- DO NOT USE COMPOUNDED FORM
- Protein bound
- Good penetration of most tissues
- Minimal excretion in urine
- Poor CNS penetration
What are the side effects of itraconazole?
- Less toxic than ketoconazole
- Nausea, vomiting, inappetence
- Hepatotoxicity
- Ulcerative dermatitis
- Does NOT suppress cortisol production
What is the spectrum for itraconazole?
- Histo
- Blasto
- Crypto
- Coccidiodes
- Aspergillus
Safest bet since is broad spectrum
When do you stop treatment with itraconazole?
60 days beyond resolution of clinical dz
Describe the characteristics of fluconazole
- PO administration
- Water soluble - high bioavailability
- Not extensively bound
- Good penetration of all body cavities and tissues INCLUDING CNS/CSF, eye
- Minimal metabolism
- RENAL excretion of active drug
What are the side effects of fluconazole?
Vomiting and diarrhea
Fluconazole is the drug of choice for what fungal agent?
Crypto - IF there’s ocular or CNS involvement
What is the spectrum for fluconazole?
- Crypto
- Candida
- Blasto*
- Histo*
- Minimal efficacy against Aspergillus
*less effective than itraconazole
How long is treatment with fluconazole?
Treat until (crypto) serum antigen testing is negative (usually 2 mo beyond resolution of C/S —> avg. duration = 8 mo)
Describe voriconazole
- Derivative of fluconazole - more lipophilic
- High bioavailability
- Metabolized by liver
-
More potent than Flu/Itraconazole for:
- Aspergillus
- Crypto
- Candida
Describe Posaconazole
- Analogue of itraconazole
- Good oral bioavailability - better w/ a meal
- SE: uncommon - V/D, incr liver enzymes
- there’s an extended released form
- VERY expensive
What is the spectrum of posaconazole?
- Candida
- Blasto
- Systemic aspergillus
- Histo
- Crypto
- Malassezia
As good or better than Flu or Itra
Describe Clotrimazole
- Topical imidazole - Minimal absorption when used topically
- Most commonly used for nasal Aspergillus infusion
- also used for bladder/renal pelvis infusions (Candida cystitis, renal aspergillosis)
- Caustic
- SE: irritating, erythema, airway obstruction secondary to inflammation from carrier, may prolong barbiturate anesthesia
Describe Enilconazole
- Topical triazole
- SE: irritation (when highly concentrated solutions used)
- Used for nasal Aspergillus infusions
Describe Terbinafine
- Inhibits ergosterol synthesis
- High concentrations in skin and nails
- Low concentrations in the lung
- High oral bioavailability (enhanced w/ fatty meal)
- Hepatic metabolism; 70% renally excreted
What are the side effects of terbinafine?
- Vomiting, diarrhea
- hepatotoxicity
- neutropenia, pancytopenia
What is the spectrum of terbinafine?
- Hyphal organisms
- Aspergillus
- Sporothrix
- Dermatophytes
- Pythium?
-
Poorly effective vs. yeast or dimorphism organisms
- Histo
- Blasto
What do cell wall synthesis inhibitors target?
- Chitin
- Chitosan
- Glucan
- Mannan
**polysaccharides making up fungal cell wall
What is the MOA of echinocandins?
Inhibit gluconate synthesis
Describe Caspofungin, Micafungin, and Anidulafungin
- Glucan inhibitors
- Low oral bioavailability
- Hepatic metabolism
- Effective against invasive candidiasis and Aspergillus (esp. resistant to AMB/triazoles)
- May have some efficacy vs. pythium
- SE: fever, urticaria, pruritus, V/D, incr liver enzymes
- VERY expensive
Describe mefenoxam
- Agricultural fungicide - plant pathogen oomycetes
- Inhibits RNA polymerase
- Not available for dogs (yet)
Itraconazole is the preferred 1st choice antifungal for which fungal organisms?
- Blasto
- Histo
- Coccidiodes
- Systemic Aspergillus
Amphotericin B has poor penetration of what tissues?
- Bones
- Brain/CSF
- Aqueous/vitreous humor
Describe iodides
- supersaturated solutions: Potassium iodide and sodium iodide
- Sporothrix tx
- Cats —> side effects can be severe
- Not commonly used
What are two examples of chitin synthesis inhibitors?
Lufenuron and Nikkomycin
- questionable efficacy for dermatophytes and coccidiomycosis
- no longer used
Why is the University of Texas fungal drug panel not really worth it?
- B/c it gives you the MIC, not the concentration required to KILL the organism
- there’s no established breakpoints for antifungals (no CLSI criteria)
- takes 2-4 weeks
- $$$
When might you consider using the U Texas fungal sensitivity test?
- Systemic aspergillosis
- Non-responsive infection
- Minimal $$ constraints
Describe griseofulvin
- MOA: disrupts mitosis
- Variable absorption - give with fatty meal
- Ultramicrosize = incr absorption
- Can be used to treat dermatophyosis with topical
What are the side effects of griseofulvin?
- vomiting, diarrhea
- anorexia
- bone marrow suppression
- Teratogenic
